MBE Advance Access published January 2, 2015
Article Discoveries
The evolution and functional impact of human deletion variants shared with archaic hominin genomes Yen-Lung Lin1, Pavlos Pavlidis2, Emre Karakoc3, Jerry Ajay4, Omer Gokcumen1 Downloaded from http://mbe.oxfordjournals.org/ by guest on January 8, 2015
1
Department of Biological Sciences State University of New York at Buffalo Buffalo, New York, U.S.A. 2
Foundation of Research and Technology – Hellas Institute of Molecular Biology and Biotechnology (IMBB) Heraklion, Crete, Greece 3
Department of Evolutionary Genetics Max Planck Institute for Evolutionary Biology Plön, Germany 4
Department of Computer Science and Engineering State University of New York at Buffalo Buffalo, New York, U.S.A.
Correspondence: Omer Gokcumen, Ph.D. [email protected] Tel: 716-645-4937 Department of Biological Sciences State University of New York at Buffalo Buffalo, NY 14260-1300, U.S.A.
© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]
1
Abstract Allele sharing between modern and archaic hominin genomes has been variously interpreted to have originated from ancestral genetic structure or through non-African introgression from archaic hominins. However, evolution of polymorphic human deletions that are shared with archaic hominin genomes have yet to be studied. We identified 427 polymorphic human deletions that are shared with archaic hominin genomes, ~87% of which originated before the Human-Neandertal divergence (ancient) and only ~9% of which have been introgressed from Neandertals (introgressed). Recurrence, incomplete lineage sorting between human and chimp lineages, and hominid-specific insertions constitute the remaining ~4% of allele sharing between humans and archaic hominins.
We found 17 exonic deletions that are shared with archaic hominin genomes, including those leading to 3 fusion transcripts. The affected genes are involved in metabolism of external and internal compounds, growth and sperm formation, as well as susceptibility to psoriasis and Crohn’s disease. Our analyses suggest that these exonic deletion variants have evolved through different adaptive forces, including balancing and population specific positive selection. Our findings reveal that genomic structural variants that are shared between humans and archaic hominin genomes are common among modern humans and can influence biomedically and evolutionarily important phenotypes. Keywords: Neandertal, Denisovan, copy number variation (CNV), DMBT1, LCE3C, GHR, ACOT1, GSTT1
2
Downloaded from http://mbe.oxfordjournals.org/ by guest on January 8, 2015
We observed that ancient deletions correspond to more than 13% of all common (>5% allele frequency) deletion variation among modern humans. Our analyses indicate that the genomic landscapes of both ancient and introgressed deletion variants were primarily shaped by purifying selection, eliminating large and exonic variants.
Introduction
Archaic admixture is not the only source of ancient variation in human genome. Previous studies identified highly divergent haplotypes in the human genome, potentially indicating the presence of ancient structure in Africa that has been maintained since before the expected coalescent date for modern human genetic variation (e.g., Barreiro et al. 2005; Cagliani et al. 2008; Teixeira et al. 2014). One hypothesis for preservation of these haplotypes is that they may have been under polymorphism-conserving balancing selection (e.g., heterozygote adaptive fitness advantage). Genomic structural variants, i.e., deletions, duplications, inversions, and translocations of genomic segments, have recently been recognized as a major part of human genomic variation (Conrad et al. 2009). It has been an ongoing challenge to discover and genotype genomic structural variants (Alkan et al. 2011). However, in the last 5 years, there has been major progress in discovery and genotyping of deletion polymorphisms (1000 Genomes Project Consortium 2012). We previously described a common deletion polymorphism in modern humans that is shared with Neandertal and Denisovan genomes (Gokcumen et al. 2013). We reasoned that this deletion has evolved before Human-Neandertal/Denisovan divergence in Africa and has been maintained through balancing selection. Herein, we extend our analyses to the entire genome to identify deletion variants observed among modern humans that are shared with Neandertal and Denisovan genomes.
3
Downloaded from http://mbe.oxfordjournals.org/ by guest on January 8, 2015
The release of ancient Neandertal and Denisovan genomes allowed us to study the relationship between genomes of ancient hominids and modern humans. Neandertal and Denisovan genomes are more closely related to each other than they are to modern human genomes and they diverged from modern human ancestors approximately 500,000 years ago (Prüfer et al. 2014a). Recent studies have shown that archaic hominins, including but not limited to Neandertals and Denisovans, contributed genetic material to modern humans (Veeramah and Hammer 2014). The origin and impact of these introgressions vary geographically and involve different species (Green et al. 2010; Reich et al. 2010; Hammer et al. 2011; Lazaridis et al. 2013). The exact timing and geographical origin of these introgressions have been the focus of several recent studies (Green et al. 2010; Currat and Excoffier 2011; Wall et al. 2013; Hu et al. 2014). In 2014, two papers documented the genome-wide distribution of Neandertal alleles across modern human genomes (Sankararaman et al. 2014; Vernot and Akey 2014). These studies found that regions in modern human genomes that carry Neandertal introgressed sequences overlap with genes less than expected by chance. This implies that purifying (i.e., negative selection against deleterious phenotypes) removed some Neandertal alleles after the introgression event.
Results Identification of polymorphic human deletions that are shared with archaic hominins
Recent Neandertal (Prüfer et al. 2014a) and Denisovan (Meyer et al. 2012) sequences provide high-depth coverage (~30X) aligned to the human reference genome, the same assembly against which 1KG deletions were compiled. As such, to detect human deletion variants that are shared with archaic hominins, we simply genotyped the 1KG deletions using read-depth data from high-coverage Neandertal and Denisovan genomes. Briefly, we calculated the number of Denisovan and Neandertal reads mapping to a given interval in the human reference genome where a deletion polymorphism was previously detected among modern humans. As expected the the number of reads of these regions correlate well with size for both Neandertal and Denisovan sequences (R2=0.8582 and R2=0.8713, respectively). However, there are intervals with obviously less than expected read depth as compared to their size (Figure S1AB). These outliers suggest potential deletions in the available archaic genomes To rigorously identify these outliers, we assumed that the read-depth/size ratio in Neandertal and Denisovan genomes across these intervals follows a normal distribution (Figure 1AB) with the observed mean and standard deviation. We then identify outliers that do not fit into this distribution (p
Article Discoveries
The evolution and functional impact of human deletion variants shared with archaic hominin genomes Yen-Lung Lin1, Pavlos Pavlidis2, Emre Karakoc3, Jerry Ajay4, Omer Gokcumen1 Downloaded from http://mbe.oxfordjournals.org/ by guest on January 8, 2015
1
Department of Biological Sciences State University of New York at Buffalo Buffalo, New York, U.S.A. 2
Foundation of Research and Technology – Hellas Institute of Molecular Biology and Biotechnology (IMBB) Heraklion, Crete, Greece 3
Department of Evolutionary Genetics Max Planck Institute for Evolutionary Biology Plön, Germany 4
Department of Computer Science and Engineering State University of New York at Buffalo Buffalo, New York, U.S.A.
Correspondence: Omer Gokcumen, Ph.D. [email protected] Tel: 716-645-4937 Department of Biological Sciences State University of New York at Buffalo Buffalo, NY 14260-1300, U.S.A.
© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact [email protected]
1
Abstract Allele sharing between modern and archaic hominin genomes has been variously interpreted to have originated from ancestral genetic structure or through non-African introgression from archaic hominins. However, evolution of polymorphic human deletions that are shared with archaic hominin genomes have yet to be studied. We identified 427 polymorphic human deletions that are shared with archaic hominin genomes, ~87% of which originated before the Human-Neandertal divergence (ancient) and only ~9% of which have been introgressed from Neandertals (introgressed). Recurrence, incomplete lineage sorting between human and chimp lineages, and hominid-specific insertions constitute the remaining ~4% of allele sharing between humans and archaic hominins.
We found 17 exonic deletions that are shared with archaic hominin genomes, including those leading to 3 fusion transcripts. The affected genes are involved in metabolism of external and internal compounds, growth and sperm formation, as well as susceptibility to psoriasis and Crohn’s disease. Our analyses suggest that these exonic deletion variants have evolved through different adaptive forces, including balancing and population specific positive selection. Our findings reveal that genomic structural variants that are shared between humans and archaic hominin genomes are common among modern humans and can influence biomedically and evolutionarily important phenotypes. Keywords: Neandertal, Denisovan, copy number variation (CNV), DMBT1, LCE3C, GHR, ACOT1, GSTT1
2
Downloaded from http://mbe.oxfordjournals.org/ by guest on January 8, 2015
We observed that ancient deletions correspond to more than 13% of all common (>5% allele frequency) deletion variation among modern humans. Our analyses indicate that the genomic landscapes of both ancient and introgressed deletion variants were primarily shaped by purifying selection, eliminating large and exonic variants.
Introduction
Archaic admixture is not the only source of ancient variation in human genome. Previous studies identified highly divergent haplotypes in the human genome, potentially indicating the presence of ancient structure in Africa that has been maintained since before the expected coalescent date for modern human genetic variation (e.g., Barreiro et al. 2005; Cagliani et al. 2008; Teixeira et al. 2014). One hypothesis for preservation of these haplotypes is that they may have been under polymorphism-conserving balancing selection (e.g., heterozygote adaptive fitness advantage). Genomic structural variants, i.e., deletions, duplications, inversions, and translocations of genomic segments, have recently been recognized as a major part of human genomic variation (Conrad et al. 2009). It has been an ongoing challenge to discover and genotype genomic structural variants (Alkan et al. 2011). However, in the last 5 years, there has been major progress in discovery and genotyping of deletion polymorphisms (1000 Genomes Project Consortium 2012). We previously described a common deletion polymorphism in modern humans that is shared with Neandertal and Denisovan genomes (Gokcumen et al. 2013). We reasoned that this deletion has evolved before Human-Neandertal/Denisovan divergence in Africa and has been maintained through balancing selection. Herein, we extend our analyses to the entire genome to identify deletion variants observed among modern humans that are shared with Neandertal and Denisovan genomes.
3
Downloaded from http://mbe.oxfordjournals.org/ by guest on January 8, 2015
The release of ancient Neandertal and Denisovan genomes allowed us to study the relationship between genomes of ancient hominids and modern humans. Neandertal and Denisovan genomes are more closely related to each other than they are to modern human genomes and they diverged from modern human ancestors approximately 500,000 years ago (Prüfer et al. 2014a). Recent studies have shown that archaic hominins, including but not limited to Neandertals and Denisovans, contributed genetic material to modern humans (Veeramah and Hammer 2014). The origin and impact of these introgressions vary geographically and involve different species (Green et al. 2010; Reich et al. 2010; Hammer et al. 2011; Lazaridis et al. 2013). The exact timing and geographical origin of these introgressions have been the focus of several recent studies (Green et al. 2010; Currat and Excoffier 2011; Wall et al. 2013; Hu et al. 2014). In 2014, two papers documented the genome-wide distribution of Neandertal alleles across modern human genomes (Sankararaman et al. 2014; Vernot and Akey 2014). These studies found that regions in modern human genomes that carry Neandertal introgressed sequences overlap with genes less than expected by chance. This implies that purifying (i.e., negative selection against deleterious phenotypes) removed some Neandertal alleles after the introgression event.
Results Identification of polymorphic human deletions that are shared with archaic hominins
Recent Neandertal (Prüfer et al. 2014a) and Denisovan (Meyer et al. 2012) sequences provide high-depth coverage (~30X) aligned to the human reference genome, the same assembly against which 1KG deletions were compiled. As such, to detect human deletion variants that are shared with archaic hominins, we simply genotyped the 1KG deletions using read-depth data from high-coverage Neandertal and Denisovan genomes. Briefly, we calculated the number of Denisovan and Neandertal reads mapping to a given interval in the human reference genome where a deletion polymorphism was previously detected among modern humans. As expected the the number of reads of these regions correlate well with size for both Neandertal and Denisovan sequences (R2=0.8582 and R2=0.8713, respectively). However, there are intervals with obviously less than expected read depth as compared to their size (Figure S1AB). These outliers suggest potential deletions in the available archaic genomes To rigorously identify these outliers, we assumed that the read-depth/size ratio in Neandertal and Denisovan genomes across these intervals follows a normal distribution (Figure 1AB) with the observed mean and standard deviation. We then identify outliers that do not fit into this distribution (p
